Synthesis, characterization, antibacterial evaluation, 2D-QSAR modeling and molecular docking studies for benzocaine der
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ORIGINAL ARTICLE
Synthesis, characterization, antibacterial evaluation, 2D‑QSAR modeling and molecular docking studies for benzocaine derivatives Israa Taha1 · Eman M. Keshk1 · Abdel‑Galil M. Khalil1 · Ahmed Fekri1 Received: 19 June 2020 / Accepted: 25 August 2020 © Springer Nature Switzerland AG 2020
Abstract Possible application of incorporating a well-known drug (benzocaine) with cyanoacetamide function to get a powerful synthon ethyl 4-cyanoacetamido benzoate. This synthetic intermediate was used as a precursor for the synthesis of triazine, pyridone, thiazolidinone, thiazole and thiophene scaffolds containing the benzocaine core. Facile coupling, Michael addition, condensation and nucleophilic attack reactions were used to synthesize our targets. The structural features of the synthesized scaffolds were characterized using IR, 1H NMR, 13C NMR and mass spectroscopy. The antibacterial activities against Grampositive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) were evaluated using ampicillin as a reference drug. DNA/methyl–green colorimetric assay of the DNA-binding compounds was also performed. Theoretical studies of the newly synthesized compounds based on molecular docking and QSAR study were conducted. The molecular docking studies were screened by MOE software for the more potent antibacterial agent 28b and each native ligand against four of S. aureus proteins 1jij, 2xct, 2w9s and 3t07. Graphic abstract
Keywords Benzocaine · Thiophene · 1,2,4-Triazine · Antibacterial · Staphylococcus aureus · Molecular operating environment (MOE)
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-020-10138-7) contains supplementary material, which is available to authorized users. * Ahmed Fekri [email protected] 1
Chemistry Department, Faculty of Science, Mansoura University, 25 El Gomhouria St, Mansoura, Dakahlia Governorate 35516, Egypt
Abbreviations QSAR Quantitative structural activity relationship MOE Molecular operating environment PCA Principle component analysis PDB Protein data bank RMSD Root-mean-square deviation MMFF94x Molecular mechanic force field HBA Hydrogen bond acceptor HBD Hydrogen bond donor Log P Lipophilicity
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Don Number of hydrogen bond donor acc Number of hydrogen bond acceptor nrotb Number of rotatable bond nviol Number of violations PSA Polar surface area TMS Tetramethylsilane
Introduction The bacterial infection is considered as one of serious issues that threaten human lives due to emerging resistance to available antibiotics introduced by multidrug-resistant bacteria. Bacterial resistance might raise the number of deaths to 10 million from the current estimated value of 700,000 annually by 2050 [1]. Consequently, the preparation of new antimicrobial agents with potent activity against microorganisms that resist drug becomes a vital demand. In particular, Staphylococcus aureus that is considered one of the most pathogeni
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